Two-piece, internal-channel osmotic delivery system flow modulator

ABSTRACT

An osmotic delivery system flow modulator includes an outer shell constructed and arranged for positioning in an opening, an inner core inserted in the outer shell, and a fluid channel having a spiral shape defined between the outer shell and the inner core. The fluid channel is adapted for delivery of an active agent formulation from the reservoir of the osmotic delivery system.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. provisional application No.60/809,451, filed May 30, 2006, the content of which is incorporatedherein in its entirety.

BACKGROUND OF THE INVENTION

The invention relates generally to osmotic delivery systems forsustained delivery of active agents in fluid environments. Moreparticularly, the invention relates to a flow modulator for deliveringan active agent from an osmotic delivery system in a fluid environment.

FIG. 1 illustrates a prior-art osmotic delivery system 40, as describedin U.S. Pat. No. 6,524,305 issued to Peterson et al. The osmoticdelivery system 40 includes an enclosure 42 containing osmotic agent 47and active agent 44. A dividing member 46 forms a partition between theosmotic agent 47 and the active agent 44. A semipermeable plug 48 isinserted into a first opening 45 of the enclosure 42. The semipermeableplug 48 selectively permits fluid to enter the interior of the enclosure42. A flow modulator 20 is inserted into a second opening 39 of theenclosure 42. The flow modulator 20 allows the active agent 44 to exitthe interior of the enclosure 42 while controlling back-diffusion offluids into the interior of the enclosure 42. When the osmotic deliverysystem 40 is disposed in a fluid environment, fluid from the exterior ofthe enclosure 42 enters the enclosure 42 through the semipermeable plug48 and permeates the osmotic agent 47, causing the osmotic agent 47 toswell. The osmotic agent 47 displaces the dividing member 46 as itswells, causing an amount of the active agent 44 to be delivered to theenvironment of use through the flow modulator 20.

In the prior-art osmotic delivery system 40 shown in FIG. 1, the outersurface of the flow modulator 20 includes a helical delivery path 32through which the active agent 44 passes from the interior to theexterior of the enclosure 42. The thread 36 which defines the helicaldelivery path 32 abuts the interior surface 43 of the enclosure 42 sothat the active agent 44 comes into contact with the interior surface 43of the enclosure 42 as it passes through the helical delivery path 32.The pitch, amplitude, cross-sectional area, and shape of the helicaldelivery path 32 are selected such that back-diffusion into theenclosure 42 from the fluid environment is minimized. Fill hole 22 andvent hole 24 are provided in the flow modulator 20. When assembling theosmotic delivery system 40, the flow modulator 20 is first inserted inthe enclosure 42. The active agent 44 is then injected into theenclosure 42 through the fill hole 22, while gases in the enclosure 42escape through the vent hole 24. Thereafter, caps 26 are inserted in theholes 22, 24 so that delivery of the active agent 44 occurs only throughthe helical delivery path 32.

From the foregoing, there continues to be a desire to provide additionalreliability and flow modulator capabilities in osmotic delivery systems.

SUMMARY OF THE INVENTION

In one aspect, the invention relates to an osmotic delivery system flowmodulator which comprises an outer shell constructed and arranged forpositioning in an opening of a reservoir of an osmotic delivery system,an inner core inserted in the outer shell, and a fluid channel having aspiral shape defined between the outer shell and the inner core, thefluid channel being adapted for delivery of an active agent formulationfrom the reservoir of the osmotic delivery system.

In another aspect, the invention relates to an osmotic delivery systemwhich comprises a reservoir, a semipermeable plug disposed at a firstend of the reservoir to selectively permit flow into the reservoir, aflow modulator disposed at a second end of the reservoir, the flowmodulator comprising an internal spiral channel adapted for delivery ofan active agent formulation contained in the reservoir to a fluidenvironment in which the osmotic delivery system operates.

In yet another aspect, the invention relates to an implantable deliverysystem for an active agent formulation which comprises a reservoir madeof an impermeable material, a first chamber in the reservoir containingan osmotic engine, a second chamber in the reservoir containing anactive agent formulation, a semipermeable plug disposed at a first endof the reservoir adjacent the first chamber, and a flow modulator asdescribed above disposed at a second end of the reservoir adjacent thesecond chamber.

Other features and advantages of the invention will be apparent from thefollowing description and the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, described below, illustrate typicalembodiments of the invention and are not to be considered limiting ofthe scope of the invention, for the invention may admit to other equallyeffective embodiments. The figures are not necessarily to scale, andcertain features and certain view of the figures may be shownexaggerated in scale or in schematic in the interest of clarity andconciseness.

FIG. 1 depicts a cross-sectional view of a prior-art osmotic deliverysystem.

FIG. 2A depicts a partial cross-sectional view of a flow modulatorhaving an inner core inserted in an outer shell and an internal spiralfluid channel formed in the inner core.

FIG. 2B depicts a partial cross-sectional view of a flow modulatorhaving an inner core inserted in an outer shell and an internal spiralfluid channel formed in the outer shell.

FIG. 2C depicts a partial cross-sectional view of a flow modulatorhaving an inner core inserted in an outer shell and an internal spiralfluid channel formed in the inner core and the outer shell.

FIG. 2D depicts a partial cross-sectional view of a flow modulatorhaving an inner core inserted in an outer shell and a flow insertincluding an internal spiral fluid channel interposed between the innercore and the outer shell.

FIG. 2E depicts a partial cross-section view of a flow modulator havingan inner core inserted in an outer shell and mating surfaces on theinner core and outer shell for preventing expulsion of the inner corefrom the outer shell.

FIG. 3 depicts a cross-sectional view of an osmotic delivery system withthe flow modulator of FIG. 2A.

FIG. 4 depicts an in vitro cumulative release of an active agent usingan osmotic delivery system according to FIG. 3.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in detail with reference to a fewpreferred embodiments, as illustrated in the accompanying drawings. Indescribing the preferred embodiments, numerous specific details are setforth in order to provide a thorough understanding of the invention.However, it will be apparent to one skilled in the art that theinvention may be practiced without some or all of these specificdetails. In other instances, well-known features and/or process stepshave not been described in detail so as not to unnecessarily obscure theinvention. In addition, like or identical reference numerals are used toidentify common or similar elements.

FIGS. 2A through 2E depict partial cross-sectional views of a flowmodulator 200 for delivery of an active agent formulation from areservoir of an osmotic delivery system. Referring to FIG. 2A, the flowmodulator 200 has an inlet side 201, which is the side that would beexposed to the active agent formulation in the reservoir of the osmoticdelivery system, and an outlet side 203, which is the side that would beexposed to a fluid environment in which the osmotic delivery systemoperates. Typically, the fluid environment is an aqueous environment,that is, the fluid environment contains water. The flow modulator 200includes an outer shell 202 and a generally cylindrical inner core 204inserted in the outer shell 202. Extending from the inlet side 201 tothe outlet side 203 of the flow modulator 200, between the outer shell202 and the inner core 204, is a fluid channel 206 having a spiralshape. All or a substantial portion of the fluid channel 206 may have aspiral shape. The fluid channel 206 is internal to the flow modulator200. The flow modulator 200 therefore forms a barrier between activeagent formulation passing through the fluid channel 206 and thereservoir of the osmotic delivery system.

In FIGS. 2A-2C, the outer surface 210 of the inner core 204 mates withthe inner surface 212 of the outer shell 202. The fluid channel 206 maybe formed in the outer surface 210 of the inner core 204, as shown inFIG. 2A, or in the inner surface 212 of the outer shell 202, as shown inFIG. 2B. Alternatively, as shown in FIG. 2C, the fluid channel 206 mayinclude a first fluid channel 206 a formed in the outer surface 210 ofthe inner core 204 and a second fluid channel 206 b formed in the innersurface 212 of the outer shell 202, wherein the first fluid channel 206a and the second fluid channel 206 b are adjacent to each other or incommunication. All or a substantial portion of each of the fluidchannels 206 a, 206 b has a spiral shape. Alternatively, as shown inFIG. 2D, a flow insert 214 may be disposed between the outer surface 210of the inner core 204 and the inner surface 212 of the outer shell 202,wherein the flow insert 214 provides the fluid channel 206. The flowinsert 214 may be a coiled tube, for example, wherein the spaces betweenthe coils of the tube serve as the fluid channel 206. Alternatively, theflow insert 214 may be a hollow cylindrical body or a sleeve in which aspiral groove is formed, where the spiral groove serves as the fluidchannel 206. The fluid channel 206 may have any desired cross-section,examples of which include circular or D shape. D-shaped fluid channelsare shown in FIGS. 2A-2E. The length of the fluid channel 206 depends onthe configuration of the osmotic delivery system and the desired releaserate. Typically, the (spiral) length of the fluid channel 206 rangesfrom 10 to 50 mm. Typically, the effective cross-sectional diameter ofthe fluid channel 206 ranges from 0.1 to 0.5 mm. These ranges are givenas examples and are not intended to limit the invention as otherwisedescribed herein.

Referring to FIGS. 2A-2D, the largest outer diameter of the inner core204 and the largest inner diameter of the outer shell 202 are selectedsuch that there is an interference fit or a seal between the outersurface 210 of the inner core 204 and the inner surface 212 of the outershell 202. This interference fit or seal confines the flow offormulation to the fluid channel 206. This interference fit or seal maybe sufficient to prevent expulsion of the inner core 204 and/or flowinsert 214 from the outer shell 202. On the other hand, in FIGS. 2A-2C,the mating portion of the surfaces 210, 212 of the inner core 204 andouter shell 202, respectively, may include features such as threadedconnection, bonded connection, welded connection, and the like toadditionally secure the inner core 204 to the outer shell 202. In FIG.2D, similar connection features may be formed between the portions ofthe inner and outer surfaces 214 a, 214 b of the flow insert 214 whichmate with the surfaces 210, 212 of the inner core 204 and outer shell202, respectively. FIG. 2E discloses an alternate method for preventingexpulsion of the inner core 204 from the outer shell 202 which includesan outer shoulder 216 on the outer surface 210 of the inner core 204abutting/engaging an inner shoulder 218 on the inner surface 212 of theouter shell 202. This prevents expulsion of the inner core 204 throughthe outlet side 203 of the flow modulator 200. The abutting/engagingsurfaces of the shoulders 216, 218 may be flat or may be tapered, asshown in FIG. 2E.

The use of abutting/engaging shoulders 216, 218 to prevent expulsion ofthe inner core 204 from the outer shell 202 into the fluid environmentin which the osmotic delivery system operates may be applied to any ofthe examples shown in FIGS. 2A-2D. Further, any of the features of theexamples shown in FIGS. 2A-2E may be interchanged and combined to makealternate examples of the flow modulator 200. For example, in FIG. 2E, achannel having a spiral shape may also be located in the inner surface212 of the outer shell 202, as described in FIG. 2C. Or, in FIG. 2D,channels having a spiral shape may also be located in the inner surface212 of the outer shell 202 and/or outer surface 210 of the inner core204, as described in FIGS. 2A and 2B, respectively, where the channelsin the outer shell 202 and/or inner core 204 would be adjacent to or incommunication with the fluid channel 206 in the flow insert 214.

Referring to FIGS. 2A-2E, the outer shell 202, the inner core 204, andthe flow insert 214 are preferably formed from a material that is inertand biocompatible. Examples of inert, biocompatible materials include,but are not limited to, non-reactive polymers and metals such astitanium, stainless steel, platinum and their alloys, andcobalt-chromium alloys. Non-reactive polymers are useful where it isdesirable to avoid interaction between the active agent formulation anda metallic material as the active agent formulation is delivered to thefluid environment in which the osmotic delivery system operates.Examples of suitable non-reactive polymers include, but are not limitedto, polyaryletherketones, such as polyetheretherketone andpolyaryletheretherketone, ultra-high molecular weight polyethylene,fluorinated ethylene-propylene, polymethylpentene, and liquid crystalpolymers. Preferably, at least the surfaces of the outer shell 202, theinner core 204, and the flow insert 214 which would be exposed to theactive agent formulation as the active agent formulation flows throughthe fluid channel 206 are made of or coated with a material that wouldnot have a detrimental effect on the active agent formulation. In apreferred example, the aforementioned surfaces are made of anon-metallic material that is inert and biocompatible. Such non-metallicmaterial could be a non-reactive polymer, examples of which are givenabove.

The length, the cross-sectional shape, and flow area of the fluidchannel 206 may be selected such that the average linear velocity of theactive agent formulation through the fluid channel 206 is higher thanthat of the linear inward influx of materials due to diffusion orosmosis from the fluid environment in which the osmotic delivery systemoperates. This would have the effect of attenuating or moderating backdiffusion, which if not controlled could contaminate the active agentformulation in the osmotic delivery system. The release rate of theactive agent formulation can be modified by modifying the geometry ofthe fluid channel 206, as described below.

The convective flow of an active agent through the fluid channel 206 isdetermined by the pumping rate of the osmotic delivery system and theconcentration of the active agent in the active agent formulation in thereservoir of the osmotic delivery system. The convective flow may beexpressed as follows:

Q _(ca)=(Q)(C _(a))  (1)

where Q_(ca) is the convective transport of beneficial in mg/day, Q isthe overall convective transport of the active agent formulation incm³/day, and C_(a) is the concentration of active agent in the activeagent formulation within the reservoir of the osmotic delivery system inmg/cm³.

The diffusive flow of active agent out of the fluid channel 206 is afunction of active agent concentration and diffusivity andcross-sectional shape and length of the fluid channel 206. The diffusiveflow may be expressed as follows:

$\begin{matrix}{Q_{da} = \frac{D\; \pi \; r^{2}\Delta \; C_{a}}{L}} & (2)\end{matrix}$

where Q_(da) is the diffusive transport of the active agent in mg/day, Dis the diffusivity through the fluid channel 206 in cm²/day, r is theeffective inner radius of the fluid channel 206 in cm, ΔC_(a) is thedifference between the concentration of the active agent in the activeagent formulation in the reservoir of the osmotic delivery system andthe concentration of the active agent in the fluid environment outsideof the delivery orifice 205 of the flow modulator 200 in mg/cm³, and Lis the (spiral) length of the fluid channel 206 in cm.

In general, the concentration of active agent in the active agentformulation in the osmotic delivery system is much greater than theconcentration of the active agent in the fluid environment of use suchthat the difference, ΔC_(a) can be approximated by the concentration ofthe active agent within the active agent formulation in the osmoticdelivery system, C_(a). Thus:

$\begin{matrix}{Q_{da} = \frac{D\; \pi \; r^{2}C_{a}}{L}} & (3)\end{matrix}$

It is generally desirable to keep diffusive flux of the active agentmuch less than convective flow of the active agent. This is representedas follows:

$\begin{matrix}{\frac{Q_{da}}{Q_{ca}} = {\frac{D\; \pi \; r^{2}C_{a}}{{QC}_{a}L} = {\frac{D\; \pi \; r^{2}}{QL} < 1}}} & (4)\end{matrix}$

Equation (4) indicates that the relative diffusive flux decreases withincreasing volumetric flow rate and path length, increases withincreasing diffusivity and channel radius, and is independent of activeagent concentration.

The diffusive flux of water where the fluid channel 206 opens into theosmotic delivery system can be approximated as follows:

Q _(wd)(res)=C _(o) Q _(e) ^((-QL/D) ^(w) ^(A))  (5)

where C_(o) is the concentration profile of water in mg/cm³, Q is themass flow rate in mg/day, L is the length of the fluid channel 206 incm, D_(w) is the diffusivity of water through the material in the fluidchannel 206 in cm²/day, and A is the cross-sectional area of the fluidchannel 206 in cm².

The hydrodynamic pressure drop across the delivery orifice can becalculated as follows:

$\begin{matrix}{{\Delta \; P} = \frac{8{QL}\; \mu}{\pi \; r^{4\;}}} & (6)\end{matrix}$

where Q is the mass flow rate in mg/day, L is the length of the spiralfluid channel in cm, μ is the viscosity of the formulation, and r is theeffective inner radius of the fluid channel in cm.

FIG. 3 shows an osmotic delivery system 300 including the flow modulator200. Although the osmotic delivery system 300 is shown with the flowmodulator 200 of FIG. 2A, it should be clear that any of the flowmodulators 200 shown in FIGS. 2A-2E may be used with the osmoticdelivery system 300. The osmotic delivery system 300 includes areservoir 302, which may be sized such that it can be implanted within abody. The reservoir 302 has open ends 304, 306. The flow modulator 200is inserted in the open end 304. A semipermeable plug 308 is inserted inthe open end 306.

The semipermeable plug 308 is a membrane that controls rate of flow offluid from the fluid environment in which the osmotic delivery systemoperates into the reservoir 302. The semipermeable plug 308 allows fluidfrom the fluid environment to enter the reservoir 302. Compositions inthe reservoir 302 are prevented from flowing out of the reservoir 302through the semipermeable plug 308 because of the semipermeable natureof the semipermeable plug 308. The semipermeable plug 308 may beinserted partially or fully into the open end 306. In the former case,the semipermeable plug 308 may include an enlarged end portion 308 awhich acts as a stop member engaging an end of the reservoir 302. Theouter surface 308 b of the semipermeable plug 308 may have protrusionsor ribs 308 c that engage the inner surface 310 of the reservoir 302,thereby locking the semipermeable plug 308 to the reservoir 302 andallowing a seal to be formed between the reservoir 302 and thesemipermeable plug 308. The reservoir 302 may also include undercutswhich receive the protrusions 308 c on the semipermeable plug 308.Semipermeable materials for the semipermeable plug 308 are those thatcan conform to the shape of the reservoir 302 upon wetting and that canadhere to the inner surface 310 of the reservoir 302. Typically, thesematerials are polymeric materials, which can be selected based on thepumping rates and system configuration requirements. Examples ofsuitable semipermeable materials include, but are not limited to,plasticized cellulosic materials, enhanced polymethyl methacrylates(PMMAs) such as hydroxyethylmethacrylate (HEMA), and elastomericmaterials, such as polyurethanes and polyamides, polyether-polyamindcopolymers, thermoplastic copolyesters, and the like. Polyurethanes aregenerally preferred.

Two chambers 312, 314 are defined inside the reservoir 302. The chambers312, 314 are separated by a partition 316, such as a slidable piston orflexible diaphragm, which is configured to fit within and make sealingcontact with the reservoir 302 and to move or deform longitudinallywithin the reservoir 302. Preferably, the partition 316 is formed of animpermeable resilient material. As an example, the partition 316 may bea slidable piston made of an impermeable resilient material and mayinclude annular ring shape protrusions 316 a that form a seal with theinner surface 310 of the reservoir 302. Osmotic engine 318 is disposedin the chamber 314 adjacent the semipermeable plug 308, and an activeagent formulation 320 is disposed in the chamber 312 adjacent the flowmodulator 200. The partition 316 isolates the active agent formulation320 from the environmental fluids that are permitted to enter thereservoir 302 through the semipermeable plug 308 such that in use, atsteady-state flow, the active agent formulation 320 is expelled throughthe fluid channel 206 at a rate corresponding to the rate at which fluidfrom the fluid environment flows into reservoir 302 through thesemipermeable plug 308.

The osmotic engine 318 may be in the form of tablets as shown. One ormore such tablets may be used. Alternatively, the osmotic engine 318 mayhave other shape, texture, density, and consistency. For example, theosmotic engine 318 may be in powder or granular form. The osmotic engine318 may include an osmopolymer. Osmopolymers are hydrophilic polymersthat can imbibe aqueous fluids, such as water and biological fluids, andupon imbibing aqueous fluids swell or expand to an equilibrium state andretain a significant portion of the imbibed fluid. Osmopolymers swell orexpand to a very high degree, usually exhibiting 2 to 50 fold volumeincrease. Osmopolymers may or may not be cross-linked. Preferredosmopolymers are hydrophilic polymers that are lightly cross-linked,such cross-links being formed by covalent or ionic bonds or residuecrystalline regions after swelling. Osmopolymers can be of plant, animalor synthetic origin. Examples of osmopolymers or hydrophilic polymerssuitable for use in the osmotic engine 318 include, but are not limitedto, poly (hydroxy-alkyl methacrylate) having a molecular weight of from30,000 to 5,000,000; polyvinylpyrrolidone (PVP) having a molecularweight of from 10,000 to 360,000; anionic and cationic hydrogels;polyelectrolytes complexes; polyvinyl alcohol having a low acetateresidual, cross-linked with glyoxal, formaldehyde, or glutaraldehyde andhaving a degree of polymerization of from 200 to 30,000, a mixture ofmethyl cellulose, cross-linked agar and carboxymethyl cellulose; amixture of hydroxypropyl methylcellulose and sodiumcarboxymethylcellulose; a mixture of hydroxypropyl ethylcellulose andsodium carboxymethyl cellulose; sodium carboxymethylcellulose; potassiumcarboxymethylcellulose; a water insoluble, water swellable copolymerformed from a dispersion of finely divided copolymer of maleic anhydridewith styrene, ethylene, propylene, butylene or isobutylene cross-linkedwith from 0.001 to about 0.5 moles of saturated cross-linking agent permole of maleic anhydride per copolymer; water swellable polymers ofN-vinyl lactams; polyoxyethylene-polyoxypropylene gel;polyoxybutylene-polyethylene block copolymer gel; carob gum; polyacrylicgel; polyester gel; polyuria gel; polyether gel; polyamide gel;polycellulosic gel; polygum gel; and initially dry hydrogels that imbibeand absorb water which penetrates the glassy hydrogel and lowers itsglass temperature. Other examples of osmopolymers include polymers thatform hydrogels, such as CARBOPOL®, acidic carboxypolymer, a polymer ofacrylic and cross-linked with a polyallyl sucrose, also known ascarboxypolymethylene and carboxyvinyl polymer having a molecular weightof 250,000 to 4,000,000; CYNAMER® polyacrylamides; cross-linked waterswellable indene-maleic anhydride polymers; GOOD-RITE® polyacrylic acidhaving a molecular weight of 80,000 to 200,000; POLYOX® polyethyleneoxide polymer having a molecular weight of 100,000 to 5,000,000 andhigher; starch graft copolymers; AQUA-KEEPS® acrylate polymerpolysaccharides composed of condensed glucose units such as diestercross-linked polygluran; and the like. The osmotic engine 318 may alsoinclude an osmagent either in addition to or in lieu of the osmopolymer.Osmagents include inorganic and organic compounds that exhibit anosmotic pressure gradient across a semipermeable wall against anexternal fluid. Osmagents imbibe fluid into the osmotic system, therebymaking available fluid to push against the formulation for deliverythrough the flow modulator. Osmagents are also known as osmoticallyeffective compounds or solutes. Osmagents useful in the osmotic engine318 include magnesium sulfate, magnesium chloride, sodium chloride,potassium sulfate, sodium sulfate, lithium sulfate, potassium acidphosphate, mannitol, urea, inositol, magnesium succinate, tartaric acid,carbohydrates such as raffinose, sucrose, glucose, lactose, sorbitol,and mixtures thereof.

The active agent formulation 320 may include one or more active agents.The active agent may be any physiologically or pharmacologically activesubstance, particularly those known to be delivered to the body of ahuman or an animal, such as medicaments, vitamins, nutrients, or thelike. Active agents which may be delivered by the osmotic deliverysystem 300 through the flow modulator 200 include, but are not limitedto, drugs that act on infectious diseases, chronic pain, diabetes, theperipheral nerves, adrenergic receptors, cholinergic receptors, theskeletal muscles, the cardiovascular system, smooth muscles, the bloodcirculatory system, synoptic sites, neuroeffector junctional sites,endocrine and hormone systems, the immunological system, thereproductive system, the skeletal system, autacoid systems, thealimentary and excretory systems, the histamine system and the centralnervous system. Suitable agents may be selected from, for example,proteins, enzymes, hormones, polynucleotides, nucleoproteins,polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids,analgesics, local anesthetics, antibiotic agents, anti-inflammatorycorticosteroids, ocular drugs and synthetic analogs of these species.Preferred active agents include macromolecules (proteins and peptides)and active agents that are highly potent. The active agent can bepresent in a wide variety of chemical and physical forms, such assolids, liquids and slurries. In addition to the one or more activeagents, the formulation 320 may optionally include pharmaceuticallyacceptable carriers and/or additional ingredients such as antioxidants,stabilizing agents, buffers, and permeation enhancers.

Materials that are used for the reservoir 302 should be sufficientlyrigid to withstand expansion of the osmotic engine 318 without changingits size or shape. Further, the materials should ensure that thereservoir 302 will not leak, crack, break, or distort under stress towhich it could be subjected during implantation or under stresses due tothe pressures generated during operation. The reservoir 302 may beformed of inert, biocompatible, natural or synthetic materials which areknown in the art. The material of the reservoir 302 may or may notbioerodible. A material that is bioerodible will at least in partdissolve, degrade, or otherwise erode in the fluid environment of use.Preferably, the material of the reservoir 302 is non-bioerodible.Generally, preferred materials for the reservoir 302 are thoseacceptable for human implantation. Preferably, the material of thereservoir 302 is impermeable, particularly when stability of theformulation in the reservoir 302 is sensitive to the fluid environmentof use. Examples of materials suitable for the reservoir 302 includenon-reactive polymers or biocompatible metals or alloys. Examples ofnon-reactive polymers for the reservoir 302 include, but are not limitedto, acrylonitrile polymers such as acrylonitrile-butadiene-styreneterpolymer; halogenated polymers such as polytetrafluoroethylene,polychlorotrifluoroethylene, copolymer tetrafluoroethylene andhexafluoropropylene; polyimide; polysulfone; polycarbonate;polyethylene; polypropylene; polyvinylchloride-acrylic copolymer;polycarbonate-acrylonitrile-butadiene-styrene; and polystyrene. Examplesof metallic materials for the reservoir 302 include, but are not limitedto, stainless steel, titanium, platinum, tantalum, gold, and theiralloys, as well as gold-plated ferrous alloys, platinum-plated ferrousalloys, cobalt-chromium alloys and titanium nitride coated stainlesssteel. For size-critical applications, high payload capability, longduration applications, and applications where the formulation issensitive to body chemistry at the implantation site, the reservoir 302is preferably made of titanium or a titanium alloy having greater than60%, often greater than 85% titanium.

The diameter of the flow modulator 200 may be selected such that theflow modulator 200 can be press-fitted into the open end 304 of thereservoir 302. It is also possible to include features such as threadson the outer surface 220 of the outer shell 202 and the inner surface310 of the reservoir 302 for securing the flow modulator 200 to thereservoir 302.

The following examples are illustrative of the invention and are not tobe construed as limiting the invention as otherwise described herein.

An osmotic delivery system, as illustrated in FIG. 3, containinginterferon-omega (IFN-ω) for the treatment of, for example, hepatitis Cwas assembled from the following components: (i) reservoir made ofimplant grade titanium alloy and having undercuts at an end thereof,(ii) osmotic engine including two cylindrical tablets, each tabletincluding primarily sodium chloride salt with cellulosic and povidonebinders, (iii) piston, (iv) semipermeable plug made of polyurethane andhaving retaining ribs that mate with undercuts in reservoir, (v) flowmodulator having a spiral internal flow channel with a D-shapedcross-section, a diameter of 0.25 mm, and a spiral length of 35 mm, and(vi) a suspension formulation including a particle formulation of IFN-ωsuspended in a non-aqueous vehicle.

Reservoirs of several osmotic delivery systems, as described above, werefilled with 150-μL of the suspension formulation. The semipermeable plugends of the osmotic delivery systems were placed into glass vials filledwith phosphate buffer solution (PBS), and the flow modulator ends of theosmotic delivery systems were placed into glass vials filled with anaqueous release media. The systems were stored or incubated at 5° C. or30° C., respectively. At specified time points, the release media wasremoved and exchanged for fresh solution. The sampled release media wasanalyzed for active agent content using Reversed Phase High PerformanceLiquid Chromatography (RP-HPLC). FIG. 4 shows in vitro cumulativerelease of IFN-ω over 6 months.

The invention may provide the following advantages. The two-piece flowmodulator enables flexibility in design and manufacturability of theflow modulator. The outer shell is not integral with the reservoir andenables the channel in the flow modulator to be inspected prior toinsertion of the flow modulator in the reservoir. The two-piece flowmodulator minimizes additional mechanical forces on the channel duringinsertion of the flow modulator in the reservoir. The two-piece flowmodulator enables flexibility to optimize the dimensions of the fluidchannel by changing the channel on the inner core or flow insert whilemaintaining a common outer sleeve.

While the invention has been described with respect to a limited numberof embodiments, those skilled in the art, having benefit of thisdisclosure, will appreciate that other embodiments can be devised whichdo not depart from the scope of the invention as disclosed herein.Accordingly, the scope of the invention should be limited only by theattached claims.

1-20. (canceled)
 21. A method of making an implantable, osmotic deliverysystem for an active agent formulation, comprising: positioning a pistonwithin a reservoir, the piston defining within the reservoir a firstchamber and a second chamber, wherein the reservoir is made of animpermeable, metallic material; positioning an osmotic engine within thefirst chamber; positioning a semipermeable plug in a first opening at afirst end of the reservoir, adjacent the osmotic engine; filling thesecond chamber with the active agent formulation, the active agentformulation comprising an active agent; and positioning a flow modulatorin a second opening at a second end of the reservoir adjacent the activeagent formulation, the flow modulator comprising an outer shellconstructed and arranged for positioning in the second opening of thereservoir of the osmotic delivery system, wherein the outer shellcomprises an inner surface and the outer shell is made of anon-metallic, non-reactive polymer material; an inner core inserted inthe outer shell, wherein the inner core comprises an outer surface andthe inner core is made of a non-metallic, non-reactive polymer material;and an internal fluid channel comprising a spiral shape defined betweenthe outer shell and the inner core, wherein the fluid channel is (i)formed on the outer surface of the inner core that mates with the innersurface of the outer shell, (ii) formed on the inner surface of theouter shell that mates with the outer surface of the inner core, or(iii) formed on the outer surface of the inner core that mates with theinner surface of the outer shell and formed on the inner surface of theouter shell that mates with the outer surface of the inner core.
 22. Themethod of claim 21, wherein the outer shell sealingly engages the innercore.
 23. The method of claim 21, wherein the non-metallic, non-reactivepolymer material of the outer shell and the inner core comprises amaterial selected from the group consisting of a polyaryletherketone, anultra-high molecular weight polyethylene, a fluorinatedethylene-propylene, a polymethylpentene, and a liquid crystal polymer.24. The method of claim 23, wherein the polyaryletherketone ispolyetheretherketone or polyaryletheretherketone.
 25. The method ofclaim 21, wherein the inner core further comprises an outer shoulder andthe outer shell further comprises an inner shoulder, wherein the outershoulder and the inner shoulder engage to prevent expulsion of the innercore from the outer shell.
 26. The method of claim 25, wherein thenon-metallic, non-reactive polymer material of the outer shell and theinner core comprises a material selected from the group consisting of apolyaryletherketone, an ultra-high molecular weight polyethylene, afluorinated ethylene-propylene, a polymethylpentene, and a liquidcrystal polymer.
 27. The method of claim 26, wherein thepolyaryletherketone is polyetheretherketone or polyaryletheretherketone.28. The method of claim 21, wherein an effective cross-sectionaldiameter of the fluid channel ranges from 0.1 mm to 0.5 mm.
 29. Themethod of claim 21, wherein a length of the fluid channel ranges from 10mm to 50 mm.
 30. The method of claim 21, wherein the active agentcomprises a protein or a peptide.
 31. The method of claim 21, whereinthe flow modulator is press-fitted into the second opening at the secondend of the reservoir.
 32. The method of claim 21, wherein the metallicmaterial of the reservoir comprises a material selected from the groupconsisting of gold-plated ferrous alloys, platinum-plated ferrousalloys, cobalt-chromium alloys, and titanium nitride coated stainlesssteel.
 33. The method of claim 21, wherein the metallic material of thereservoir comprises a material selected from the group consisting ofstainless steel, titanium, platinum, tantalum, gold, and alloys thereof.34. The method of claim 21, wherein the metallic material of thereservoir comprises titanium or a titanium alloy.
 35. The method ofclaim 21, wherein the piston comprises an impermeable, resilientmaterial.
 36. The method of claim 21, wherein the semipermeable plugcomprises a material selected from the group consisting of plasticizedcellulosic materials, enhanced polymethyl methacrylates, elastomericmaterials, polyether-polyamide copolymers, and thermoplasticcopolyesters.
 37. The method of claim 21, wherein the semipermeable plugcomprises a polyurethane.
 38. A method of making an implantable, osmoticdelivery system for an active agent formulation, comprising: positioninga piston within a reservoir, the piston defining within the reservoir afirst chamber and a second chamber, wherein the reservoir is made of animpermeable, metallic material; positioning an osmotic engine within thefirst chamber; positioning a semipermeable plug in a first opening at afirst end of the reservoir, adjacent the osmotic engine; filling thesecond chamber with the active agent formulation, the active agentformulation comprising an active agent; and positioning a flow modulatorin a second opening at a second end of the reservoir adjacent the activeagent formulation, the flow modulator comprising an outer shellconstructed and arranged for positioning in the second opening of thereservoir of the osmotic delivery system, wherein the outer shellcomprises an inner surface and the outer shell is made of a non-metallicmaterial; an inner core inserted in the outer shell, wherein the innercore comprises an outer surface and the inner core is made of anon-metallic material; and an internal fluid channel comprising (a) aspiral shape defined between the outer shell and the inner core, and (b)an effective cross-sectional diameter of from 0.1 mm to 0.5 mm, whereinthe fluid channel is (i) formed on the outer surface of the inner corethat mates with the inner surface of the outer shell, (ii) formed on theinner surface of the outer shell that mates with the outer surface ofthe inner core, or (iii) formed on the outer surface of the inner corethat mates with the inner surface of the outer shell and formed on theinner surface of the outer shell that mates with the outer surface ofthe inner core.
 39. The method of claim 38, wherein the outer shellsealingly engages the inner core.
 40. The method of claim 38, whereinthe non-metallic material of the outer shell and the inner corecomprises a material selected from the group consisting of apolyaryletherketone, an ultra-high molecular weight polyethylene, afluorinated ethylene-propylene, a polymethylpentene, and a liquidcrystal polymer.
 41. The method of claim 40, wherein thepolyaryletherketone is polyetheretherketone or polyaryletheretherketone.42. The method of claim 38, wherein the inner core further comprises anouter shoulder and the outer shell further comprises an inner shoulder,wherein the outer shoulder and the inner shoulder engage to preventexpulsion of the inner core from the outer shell.
 43. The method ofclaim 42, wherein the non-metallic material of the outer shell and theinner core comprises a material selected from the group consisting of apolyaryletherketone, an ultra-high molecular weight polyethylene, afluorinated ethylene-propylene, a polymethylpentene, and a liquidcrystal polymer.
 44. The method of claim 43, wherein thepolyaryletherketone is polyetheretherketone or polyaryletheretherketone.45. The method of claim 38, wherein a length of the fluid channel rangesfrom 10 mm to 50 mm.
 46. The method of claim 38, wherein the activeagent comprises a protein or a peptide.
 47. The method of claim 38,wherein the flow modulator is press-fitted into the second opening atthe second end of the reservoir.
 48. The method of claim 38, wherein themetallic material of the reservoir comprises a material selected fromthe group consisting of gold-plated ferrous alloys, platinum-platedferrous alloys, cobalt-chromium alloys, and titanium nitride coatedstainless steel.
 49. The method of claim 38, wherein the metallicmaterial of the reservoir comprises a material selected from the groupconsisting of stainless steel, titanium, platinum, tantalum, gold, andalloys thereof.
 50. The method of claim 38, wherein the metallicmaterial of the reservoir comprises titanium or a titanium alloy. 51.The method of claim 38, wherein the piston comprises an impermeable,resilient material.
 52. The method of claim 38, wherein thesemipermeable plug comprises a material selected from the groupconsisting of plasticized cellulosic materials, enhanced polymethylmethacrylates, elastomeric materials, polyether-polyamide copolymers,and thermoplastic copolyesters.
 53. The method of claim 38, wherein thesemipermeable plug comprises a polyurethane.
 54. A method of making animplantable, osmotic delivery system for an active agent formulation,comprising: positioning a piston within a reservoir, the piston definingwithin the reservoir a first chamber and a second chamber, wherein thereservoir is made of an impermeable, metallic material; positioning anosmotic engine within the first chamber; positioning a semipermeableplug in a first opening at a first end of the reservoir, adjacent theosmotic engine; filling the second chamber with the active agentformulation, the active agent formulation comprising an active agent;and positioning a flow modulator in a second opening at a second end ofthe reservoir adjacent the active agent formulation, the flow modulatorcomprising an outer shell constructed and arranged for positioning inthe second opening of the reservoir of the osmotic delivery system,wherein the outer shell comprises an inner surface and the outer shellis made of a non-metallic, non-reactive polymer material; an inner coreinserted in the outer shell, wherein the inner core comprises an outersurface and the inner core is made of a non-metallic, non-reactivepolymer material; and an internal fluid channel comprising (a) a spiralshape defined between the outer shell and the inner core, and (b) aneffective cross-sectional diameter of from 0.1 mm to 0.5 mm, wherein thefluid channel is (i) formed on the outer surface of the inner core thatmates with the inner surface of the outer shell, (ii) formed on theinner surface of the outer shell that mates with the outer surface ofthe inner core, or (iii) formed on the outer surface of the inner corethat mates with the inner surface of the outer shell and formed on theinner surface of the outer shell that mates with the outer surface ofthe inner core.
 55. The method of claim 54, wherein the outer shellsealingly engages the inner core.
 56. The method of claim 54, whereinthe non-metallic, non-reactive polymer material of the outer shell andthe inner core comprises a material selected from the group consistingof a polyaryletherketone, an ultra-high molecular weight polyethylene, afluorinated ethylene-propylene, a polymethylpentene, and a liquidcrystal polymer.
 57. The method of claim 56, wherein thepolyaryletherketone is polyetheretherketone or polyaryletheretherketone.58. The method of claim 54, wherein the inner core further comprises anouter shoulder and the outer shell further comprises an inner shoulder,wherein the outer shoulder and the inner shoulder engage to preventexpulsion of the inner core from the outer shell.
 59. The method ofclaim 58, wherein the non-metallic, non-reactive polymer material of theouter shell and inner core comprises a material selected from the groupconsisting of a polyaryletherketone, an ultra-high molecular weightpolyethylene, a fluorinated ethylene-propylene, a polymethylpentene, anda liquid crystal polymer.
 60. The method of claim 59, wherein thepolyaryletherketone is polyetheretherketone or polyaryletheretherketone.61. The method of claim 54, wherein a length of the fluid channel rangesfrom 10 mm to 50 mm.
 62. The method of claim 54, wherein the activeagent comprises a protein or a peptide.
 63. The method of claim 54,wherein the flow modulator is press-fitted into the second opening atthe second end of the reservoir.
 64. The method of claim 54, wherein themetallic material of the reservoir comprises a material selected fromthe group consisting of gold-plated ferrous alloys, platinum-platedferrous alloys, cobalt-chromium alloys, and titanium nitride coatedstainless steel.
 65. The method of claim 54, wherein the metallicmaterial of the reservoir comprises a material selected from the groupconsisting of stainless steel, titanium, platinum, tantalum, gold, andalloys thereof.
 66. The method of claim 54, wherein the metallicmaterial of the reservoir comprises titanium or a titanium alloy. 67.The method of claim 54, wherein the piston comprises an impermeable,resilient material.
 68. The method of claim 54, wherein thesemipermeable plug comprises a material selected from the groupconsisting of plasticized cellulosic materials, enhanced polymethylmethacrylates, elastomeric materials, polyether-polyamide copolymers,and thermoplastic copolyesters.
 69. The method of claim 54, wherein thesemipermeable plug comprises a polyurethane.